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ABSTRACT WORD COUNT: 208 words

WORD COUNT: (excluding Abstract and References) 2,434 words

SUMMARY STATEMENT OF COI DISCLOSURES: While Drs. De Torres, Miravitlles

and Celli have served on Industry advisory boards for companies that make COPD

drugs, and Drs. Soriano, Alfageme, Almagro, Casanova, Soler-Cataluña, de Torres,

Miravitlles, and Celli have given industry sponsored lectures during the period 2010-

2012, industry did not pay/ fund this study. In-full individual disclosures by all authors

are found in the appendix. We declare that none of the authors have any other conflicts

of interest to disclose regarding the contents of this manuscript.

Distribution and prognostic validity of the new GOLD grading

classification

Joan B. Soriano, M.D.,1 Inmaculada Alfageme, M.D.,2 Pere Almagro, M.D.,3

Ciro Casanova, M.D.,4 Cristobal Esteban, M.D.,5 Juan J. Soler-Cataluña, M.D.,6

Juan P. de Torres, M.D.,7 Pablo Martinez-Camblor, Ph.D.,8 Marc Miravitlles,

M.D.,9 Bartolome R. Celli, M.D.,10 and Jose M. Marin, M.D.11

1 Fundación Caubet-Cimera Illes Balears, Bunyola, Spain; 2 Hospital

Universitario Valme, Sevilla; 3 Internal Medicine, Hospital Universitari Mutua de

Terrassa, Universitat de Barcelona, Barcelona; 4 Hospital Nuestra Señora de la

Candelaria, Tenerife; 5 Hospital Galdakao-Usansolo, Galdakao, Bizkaia

6 Unidad de Neumología, Servicio de Medicina Interna, Hospital General de

Requena, Valencia; 7 Clınica Universidad de Navarra, Pamplona; 8 CAIBER,

Oficina de Investigación Biosanitaria de Asturias, Oviedo; 9 Institut

d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic,

Barcelona, Spain; 10 Harvard University, Brigham and Women's Hospital,

Pulmonary and Critical Care Medicine, Boston, MA, USA; 11 Hospital

Universitario Miguel Servet, Zaragoza, Spain

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Author for correspondence: Dr. Joan B Soriano

Director, Program of Epidemiology & Clinical Research

CIMERA. Recinte Hospital Joan March, Carretera Soller Km 12.

07110 - Bunyola, Illes Balears; Spain

Email: [email protected]

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ADDITIONAL FILE INFORMATION

FILE DATE: August 10, 2012

ILLUSTRATIONS: 3 tables and 3 figures (online appendix with one e-table and

one e-figure)

NUMBER OF REFERENCES: 33 references

FINANCIAL DISCLOSURE INFORMATION: No funding was required/available

for COCOMICS.

ACKNOWLEDGMENTS & AUTHOR’S CONTRIBUTIONS: JBS had the

original idea; IA, PA, CC, CE, JJ S-C, JP de T, BRC and JMM collected the

clinical data. PMC, JBS, MM, and JMM developed the plan of analysis; JBS

drafted the report, and all co-authors contributed to and approved this

manuscript.

SHORT RUNNING HEAD: New GOLD grading

KEYWORDS: COPD, GOLD, grading, population, severity, survival

Email distribution list: [email protected]; [email protected];

[email protected]; [email protected]; [email protected];

[email protected]; [email protected]; [email protected];

[email protected]; [email protected] ; [email protected]; jbsoriano@caubet-

cimera.es

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ABSTRACT

Background: The new GOLD update includes airflow limitation, history of

COPD exacerbations and symptoms to classify and grade COPD severity. We

aimed to determine their distribution in eleven, well defined COPD cohorts, and

their prognostic validity up to 10 years to predict time to death.

Methods: Spirometry in all eleven cohors was post-bronchodilator. Survival

analysis and C-statistics were used to compare the two GOLD systems by

varying time points.

Results: Of 3,633 patients, 1,064 (33.6%) were in new GOLD patient group A

(low risk, less symptoms); 515 (16.3%) were B (low risk, more symptoms); 561

(17.7%) were C (high risk, less symptoms); and 1,023 (32.3%) were D (high

risk, more symptoms). There was great heterogeneity of this distribution within

the cohorts (Chi2 p value < 0.01). No differences were seen in the C statistics of

old versus new GOLD grading to predict mortality at one year (0.635 vs. 0.639,

p=0.53, at three years (0.637 vs. 0.645, p=0.21) or at 10 years (0.639 vs. 0.642,

p=0.76).

Conclusions: The new GOLD grading produces an uneven split of the COPD

population, one third each in A and D patient groups, and its prognostic validity

to predict time to death is no different than the old GOLD staging based in

spirometry only.

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ABBREVIATION LIST:

ATS/ERS = American Thoracic Society/European Respiratory Society

BMI = Body mass index

COPD = Chronic obstructive pulmonary disease

COCOMICS = COllaborative COhorts to assess Multicomponent Indices of

COPD in Spain

GOLD = The Global Initiative for Chronic Obstructive Lung Disease

GP = General Practitioner

mMRC = modified Medical Research Council

6-MWT = Six-minutes walking test

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INTRODUCTION

The fundamental role played by The Global Initiative for Chronic

Obstructive Lung Disease (GOLD) from 2001 to date to influence all aspects of

chronic obstructive pulmonary disease (COPD) cannot be underestimated.1 It

has helped to systematize diagnosis and treatment of this condition, both in

developed and in developing countries, all aimed to reduce the individual and

population burden of COPD. COPD is considered now a common, preventable

and treatable disease, characterized by airflow limitation that is usually

progressive and associated with an enhanced chronic inflammatory response in

the airways and the lung to noxious particles or gases. Exacerbations and

comorbidities contribute to the overall severity in individual patients.2 COPD

results from inflammation and/or alterations in repair mechanisms. The "spill-

over" of inflammatory mediators from the respiratory system into the circulation

or systemic inflammation may also initiate or worsen comorbid diseases, such

as ischaemic heart disease, heart failure, osteoporosis, normocytic anaemia,

lung cancer, depression and diabetes.3

Spirometry is recognized by international clinical guidelines as the

essential test to diagnose COPD and stage severity, based on different

transformations of the FEV1 and other lung function variables. Indeed, the

GOLD report of 2001 and its update in 2006 recommended the staging of

COPD severity according to spirometry only.4 However, the new GOLD update

(as December 30, 2011) includes airflow limitation, history of COPD

exacerbations and symptoms to classify and grade COPD severity.2 Given

recent evidence on the progression and natural history of airflow limitation in

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COPD, staging was substituted for grading to assess COPD severity, in four

mutually exclusive groups (Table 1).

By conducting a patient-based pooled analysis of eleven COPD cohorts, we

aimed to determine the distribution of the new GOLD groups and their

prognostic validity to predict time to death in comparison with the old GOLD

staging.

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METHODS

Our study design is of a pooled-analysis of individual patient-data,5 from

a number of COPD patient cohorts, all in Spain: Galdakao,6 Pamplona,7

Requena,8,9 Sevilla,10 Tenerife,11 Terrassa,12,13,14 and Zaragoza15.

Comprehensive details of The COllaborative COhorts to assess

Multicomponent Indices of COPD in Spain (COCOMICS) study are available

elsewhere.16 Briefly, a minimum data set with age, gender, spirometry, and

follow-up data in all patients was required. Data were provided by the primary

investigator of each of the participating cohorts, spanning for a period of

approximately 20 years. Further details on methods applied of each study can

be found elsewhere. 6-15 Post-bronchodilator forced spirometry was performed

according to the guidelines of the American Thoracic Society/European

Respiratory Society (ATS/ERS) consensus.17 Functional dyspnea was

assessed using the modified Medical Research Council (mMRC) dyspnea

scale.18 Comorbidities were quantified by means of the Charlson index,19

excluding COPD. All participants gave their informed written consent to

participate and each study was approved by their respective ethics committee.

Statistics

All data was quality controlled centrally and a homogeneous template to

translate all coding was applied. Variables were then double-checked by each

principal investigator, and values that were considered as potential errors or

outliers were individually discussed and confirmed, or removed. Comprehensive

tabulations with ranges, mean and standard deviation of all quantitative

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variables, and percentages of all qualitative variables, were available for each

study.

We focused all analyses on time to death for all causes, as other outcomes (i.e.:

exacerbations of different types) were considered less reliably recorded. Given

the substantial patient-year exposure within the database, survival at one, three,

and up to ten years were tested to predict time to death. Standard Cox

semiparametric proportional hazards models were employed to model the time-

to-death data.20 C statistics, a measure of discrimination for survival analysis,

was employed to assess the performance of the time-to-death models.21

Heterogeneity and potential study effects were handled by running models with

the individual study as an additional stratification variable, and inferences were

by the bootstrap method.22 In all analyses, a p value below 0.05 was considered

for statistical significance.

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RESULTS We obtained data of 3,633 COPD patients from eleven cohorts in Spain. They

had an age (mean±SD) of 66.4±9.7 years, 93.3% were male and 6.7% female.

Indeed women were younger (59.8±11.0 vs. 66.9±9.5 years) and more

frequently current smokers (43.3% vs. 26.8%) than men (both p<0.05), but the

size of the female group (n=244) make us reluctant to report results by gender.

At study entry smoking exposure was substantial (53.4±26.5 pack-years), and

71.0% were former-smokers while 27.9% were still current-smokers. Most

participants were of moderate or higher spirometrical severity with a percent

predicted FEV1 of 53.8±19.4, and a Charlson index of 0.9±1.8 (Table 2). Based

on spirometry only, they were classified according to old GOLD as 368 (10.2%)

mild, 1,612 (44.8%) moderate, 1,255 (34.9%) severe, and 366 (10.2%) very

severe.

To construct the new GOLD grading criteria the following sequence was done.

Out of the total of 3,633 patients, we had data on COPD hospitalizations in

2,846 participants, spirometry in 3,601 and mMRC dyspnoea in 3,163. The at-

risk criteria (spirometry and/or COPD hospitalization) included 3.632 patients, of

which 1,773 were of high risk and therefore are completely well classified (either

C or D). Then, of the 1,859 within low risk, there were 1,283 with both criteria

(again completely well classified, either as A or B). However, the remainder,

576 (15.9%) could have their severity under-rated, as the unknown variable

could have classified them into the high risk group.

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According to the new GOLD grading, 1,064 (33.6%) were graded new GOLD

patient group A (low risk, less symptoms); 515 (16.3%) were B (low risk, more

symptoms); 561 (17.7%) were C (high risk, less symptoms); and 1,023 (32.3%)

were D (high risk, more symptoms) (e-Table 1). There was great heterogeneity

of both staging distributions within the cohorts (Figure 1) (Chi2 p value < 0.01).

There were no differences in the C statistics of old versus new GOLD staging to

predict survival at one year (0.635 vs. 0.639, p=0.53, at three years (0.637 vs.

0.645, p=0.21) or at 10 years (0.639 vs. 0.642, p=0.76). Actually, when visually

displaying the survival curves according to the new GOLD grading, it can be

seen that it takes longer than three years to separate the survival curves of

group B (low risk, more symptoms) versus group C (high risk, less symptoms)

(Figure 2). Quantitatively, the hazard ratios relative to the new GOLD A staging

were no different in B vs. C, namely group B 1.70 95%C.I (1.38-2.10), group C

1.69 95%C.I (1.39-2.08), and group D 2.79 95%C.I (2.35-3.32). There was

again great heterogeneity on the time to death according to the new GOLD

grading within the cohorts (Chi2 p value < 0.01) (e-Figure 1).

When constructing the new GOLD grading system from old GOLD, the

contribution of collapsing the spirometry criteria from four to two strata, and then

sequentially adding exacerbations and symptoms, can be seen in Table 3. The

change in C statistics at 10 years is not remarkable, from 0.639 in old GOLD, to

an actual significant decrease in GOLD I-II and III-IV at 0.617, p=0.003; then a

significant increase by adding exacerbations (C statistic 0.618, p=0.008), and a

final non-significant C statistic for the new GOLD grading of 0.642, p=0.76, as

abovementioned.

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Finally, the impact in mortality if the entry defining criteria by GOLD 2011 is

either spirometry, or exacerbations, or both is presented in Figure 3. It can be

seen that the COPD hospitalizations-only criteria had the mildest effect on

survival, followed by spirometry-only, but without statistical significance with a

hazard ratio of 0.98 and a 95% C.I. (0.68-1.41). However, both together had an

additive, deleterious effect, 1.56, 95% C.I. (1.27-1.91).

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DISCUSSION

We report that the new GOLD grading produces an uneven split of the

COPD population, one third each in A and D patient groups, while one in six

COPD patients are B and C respectively, which to our knowledge is a novel

finding. Of interest, its prognostic validity to predict time to death is no different

than the old GOLD staging based in spirometry only. We believe the new GOLD

grading makes more clinical sense, as decisions on treatment should not be

only based (they never were) on airflow limitation, but on other clinically relevant

assessments, like past exacerbations and current symptoms. However, it could

be misleading to consider that the newly proposed grading system indicates

growing severity and predicts death consistently, and we actually demonstrate

this is not the case.

The new GOLD grading was constructed by extrapolating information of

prospectively collected data from one clinical study and two large medium-term

clinical trials 23,24,25 (page 14 out of 74).2 All three have been landmark studies,

but their representativity to real-life clinical patients can be debated, and not all

had other relevant variables like exercise measured.26 We used a relatively new

tool, pooled analysis, which collects individual patient-level data and analyzes

studies as a single, new study. This has advantages over classical meta-

analyses as it avoids many of the methodological pitfalls related to classical

meta-analytic techniques that rely exclusively on published data.5

Strengths and limitations of the current study

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The COCOMICS strengths include a large sample size of nearly 16,000 person-

yr., allowing for statistical power in most sub-analyses; very few participants

were lost to follow-up, as cohorts were built from clinical practice in large

hospital centres managing these patients. Homogeneity, as all COPD patients

are Spanish, granted by law with guaranteed universal, free-of charge health

coverage up to now, giving robustness in the interpretation/assessment of

health outcomes. Internal consistency, as all investigators follow the same

COPD clinical guidelines for pharmacological and non-pharmacological

treatments. Finally, by including cohorts of patients with different origins, and

severity, we cover a diverse population

On limitations, the CAT questionnaire27 to assessing other symptoms beyond

dyspnoea was not available at the onset of all our cohorts, so we may have

underestimated symptom severity by using the mMRC only. There was no full

information on COPD hospitalization history in two cohorts (Pamplona and

Zaragoza I) losing the experience from 795 and 717 persons-yr respectively,

which corresponds to 9.5% of all follow-up data. Not all participants had data in

all variables, and key variables like milder exacerbations or cause of death were

not collected consistently or in all participants. Note that Zaragoza II contributed

one third of study participants (1,150 out of 3,633) and over one third of patient-

years (6,520 out of 15,878), adding valuable statistical power, but weighing up

substantially to one single cohort. Regrettably, history of past COPD

exacerbations and/or prospective use of health resources (emergency

department visits and hospitalizations) were not collected in all cohorts, and in

the few who collected them consistently, it was considered that methods were

too diverse to be pooled together. In particular, perhaps the most important

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limitation of our study is using hospitalizations only to determine COPD

exacerbations, rather than also outpatient episodes. We performed an a

posteriori analysis in two of the eleven cohorts in which all types of COPD

exacerbations were systematically collected and that we considered had the

greatest validity and similar definitions of ambulatory COPD exacerbations

(Online Appendix). For this re-analysis, ambulatory COPD exacerbations were

defined as those COPD exacerbations that did not require a hospitalization, that

is they only required an emergency room visit, or a GP or other doctor attention.

From the 766 individuals assessed, 114 (14.9%) would actually change group,

that is 76 (9.9%) from A to C, and 38 (5.0%) from B to D. Importantly, our

conclusions did not change, the new GOLD 2011 severity grading becoming

even less predictive of death if ambulatory COPD exacerbations were factored

in. Other limitations include: Numbers of COPD women were scanty (7%),

reflecting the reality of clinical COPD in our populations. It was not possible an

analysis on treatments, or of time-dependant variables to assess changes in

medication, smoking habits, and other. Even in the very long-term, our analyses

assumed that the patients' condition did not change from baseline, which in

some variables may not be so (medication changes, become a frequent

exacerbator, or developing a new comorbidity). Although some COPD variables

show stability and repeatability, these analyses had no regular monitoring and

re-staging or re-grading.

Likely the new GOLD grading has a different distribution in other clinical

settings. Intuitively in other tertiary centres like ours, patient group D prevails as

the most severe patients are often in the at-risk category (either by spirometry

and/or exacerbations) and will have symptoms frequently. Counterintuitively,

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patient group A will also be very frequent as moderate airflow limitation makes

the most frequent participants in most COPD clinical trials, but in this case they

are either maximally treated or accommodated to avoid efforts,28 ergo reporting

less symptoms. We can speculate than in the primary care level, there might be

a predominance of patient group B, as COPD patients should have less

frequently severe or very severe airflow limitation and experience less COPD

exacerbations, so they would not be in the at-risk categories, but they are

having symptoms as they are requesting medical care. Again counterintuitively,

it can be seen in Figure 2, that our COPD cohorts from Internal Medicine

(Terrassa I, II and III) or from a mid-size Respiratory Regional Unit (Requena I

and II), contributed the most COPD patients in patient group D. More research

by other groups reporting their group distributions will be expected. Our time to

death outcomes are less likely to be replicated by other groups, as our

experience might be difficult to match given the very long-term data and large

person-time size included in here. Our finding of no differentiation of groups B

and C before three years might be puzzling to obtain in time to death, so

perhaps time to first exacerbation could be used as an alternative. As recently

reported, severe exacerbations at any stage of COPD are associated with a

higher risk of short-term and long-term all-cause mortality,29 and the very short-

term prognosis (up to three months) is associated with comorbidities.30

The possibility of a more personalized treatment of COPD patients, according to

severity combining spirometry,31 with symptoms and exacerbations, had been

postulated previously elsewhere.32,33 We agree with the new GOLD

recommendations it is the way to move forward, although definitive thresholds

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need to be established.2 Any therapeutic decisions will remain controversial

until more evidence is built to move from earlier expert opinion.

Conclusions

We conclude that the new GOLD grading produces an uneven split of the

COPD population, one third each in A and D patient groups, and its prognostic

validity to predict time to death is no different than the old GOLD staging based

in spirometry only.

.

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INDIVIDUAL STATEMENTS OF COI DISCLOSURES: Joan B Soriano received pharmaceutical company grants from GSK in 2011 and Chiesi in 2012 via his home institution, and also participated in speaking activities, industry advisory committee, or other related activities sponsored by Almirall, Boehringer-Ingelheim, Pfizer, Chiesi, GSK, and Novartis during the period 2010-2012. Immaculada Alfageme has received speaker fees from Boehringer-Ingelheim and Pfizer during the period 2010-2012. Pere Almagro participated in speaking activities, industry advisory committee, or other related activities sponsored by Takeda-Nycomed, Almirall, Boehringer-Ingelheim, Pfizer, Chiesi, GSK, Esteve, Merck Sahrp&Dohme, and Novartis during the period 2010-2012. Ciro Casanova declares to participate in speaking activities during the period 2010-2012 related to the following industry sources: Almirall, Takeda-Nycomed, Chiesi, GSK, Novartis and declares not to have any other potential conflicts of interest to report regarding the contents of this manuscript. Juan José Soler-Cataluña participated in speaking activities, industry advisory committee, or other related activities sponsored by Almirall, AstraZeneca, Boehringer-Ingelheim, Pfizer, Ferrer, GSK, Nycomed-MSD, Novartis and Uriach during the period 2010-2012. Juan Pablo de Torres received fees for speaking activities for GSK, AstraZeneca, Novartis, MSD and Nycomed; and received consultancy fees for participating in the Nycomed and Novartis Advisory Boards during the period 2010-2012. Marc Miravitlles has received speaker fees from Boehringer-Ingelheim, Pfizer, Bayer Schering, Novartis, Talecris, Nycomed, Merck, Sharp & Dohme and Novartis and consulting fees from Boehringer Ingelheim, Pfizer, GSK, Bayer Schering, Novartis, Almirall, Merck, Sharp & Dohme and Nycomed during the period 2010-2012. Bartolome R Celli has served in the GSK sponsored ECLIPSE and the SUMMIT trial; in Advisory Boards for Astra Zeneca and Novartis; received pharmaceutical company grant monies from Astra Zeneca to his home institution; and is consultant to a pharmaceutical or medical device company and received speaker fees from GSK, AstraZeneca, Rox pharmaceutical, Almirall, and Boehringer-Ingelheim during the period 2010-2012.. All other authors (Drs. Cristobal Esteban, Pablo Martínez-Camblor and Jose M Marin) declare not to have conflicts of interest to report regarding the contents of this manuscript.

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Table 1. New GOLD grading to stage COPD severity

Ris

k

GO

LD

airflow

lim

itatio

n

4 3

(C)

(D)

≥2

Ris

k

(Exacerb

atio

ns)

2 1

(A)

(B)

1 0

mMRC <2 CAT <10

mMRC ≥2 CAT≥10

Symptoms

Legend of Table 1: Note that COCOMICS had no CAT and we used COPD hospitalizations as exacerbations Patient Group A – Low Risk, Less Symptoms: Typically GOLD 1 or GOLD 2 (Mild or Moderate airflow limitation) and/or ≤1 exacerbation per year and mMRC <2 or CAT score <10) Patient Group B – Low Risk, More Symptoms: Typically GOLD 1 or GOLD 2 (Mild or Moderate airflow limitation) and/or ≤ 1 exacerbation per year and mMRC ≥2 or CAT score ≥10) Patient Group C – High Risk, Less Symptoms: Typically GOLD 3 or GOLD 4 (Severe or Very Severe airflow limitation) and/or ≥2 exacerbations per year and mMRC <2 or CAT score <10) Patient Group D – High Risk, More Symptoms: Typically GOLD 3 or GOLD 4 (Severe or Very Severe airflow limitation) and/or ≥2 exacerbations per year and mMRC >2 or CAT score >10)

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Table 2. Demographic and clinical characteristics of patients at baseline/enrolment, of old GOLD, and new GOLD TOTAL N 3,633 Person-year, m±SD 15,878.17 Age, m±SD 66.39±9.73 Male, n (%) 3,389 (93.3) Pack-yr, m±SD 53.65±36.03 Smoking status, n (%) Former Current Never

2,532 (71.0) 996 (27.9) 38 (1.1)

BMI, m±SD 27.86±4.98 %pFEV1, m±SD 53.77±19.43 mMRC, m±SD 2.59±1.14

6-MWT, m±SD 397±130 Past COPD Exacs, m±SD 0.89±1.81 old GOLD groups, n (%) Mild Moderate Severe Very severe

368 (10.2) 1612 (44.8) 1255 (34.9) 366 (10.2)

new GOLD groups, n (%) A B C D

1,064 (33.6) 515 (16.3) 561 (17.7)

1,023 (32.3) Note: Spirometry in all eleven cohors was post-bronchodilator. NA: Not available.

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Table 3. Constructing the new GOLD grading system from the old GOLD staging. Change in C statistics at 10 years

C-Statistics P-values versus old GOLD

Old GOLD 0.639 1.00 GOLD I-II vs. III - IV 0.617 0.003 Risk (New GOLD)* 0.618 0.008 New GOLD** 0.642 0.76

NOTE: (*) Spirometry and exacerbations contribute to the variable Risk in the new GOLD staging system (two groups) (**) The new GOLD staging system is created by adding mMRC dyspnoea to the previous one, creating four groups.

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14 Almagro P, Salvadó M, Garcia-Vidal C, Rodriguez-Carballeira M, Delgado M, Barreiro B, Heredia JL, Soriano JB. Recent improvement in long-term survival after a COPD hospitalisation. Thorax 2010;65:298-302. 15 Marin JM, Soriano JB, Carrizo SJ, Boldova A, Celli BR. Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the overlap syndrome. Am J Respir Crit Care Med. 2010;182:325-31. 16 Marin JM, Alfageme I, Almagro P, Casanova C, Esteban C, Soler-Cataluña JJ, de Torres JP, Martinez-Camblor P, Miravitlles M, Celli BR, Soriano JB. Multicomponent indices to predict survival in COPD (submitted). 17 Miller MR, Hankison J, Brusasco V, Burgos R, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J 2005; 26:319-38. 18 Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax 1999;54:581-6. 19 Charlson ME, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol 1994; 47: 1245-51. 20 Cox DR, Oakes D. Analysis of Survival Data. London, England: Chapman & Hall; 1984. 21 Pencina MJ, D’Agostino RB. Overall C as a measure of discrimination in survival analysis: model specific population value and confidence interval estimation. Stat Med 2004;23:2109-2123. 22 Martínez-Camblor P, Corral N, A general bootstrap algorithm for hypothesis testing, Journal of Statistical Planning and Inferences 2012;142:589-600. 23 Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H, Tal-Singer R, Miller B, Lomas DA, Agusti A, Macnee W, Calverley P, Rennard S, Wouters EF, Wedzicha JA; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 2010;363:1128-38. 24 Decramer M, Celli B, Kesten S, Lystig T, Mehra S, Tashkin DP; UPLIFT investigators. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet. 2009;374:1171-8. 25 Jenkins CR, Jones PW, Calverley PM, Celli B, Anderson JA, Ferguson GT, Yates JC, Willits LR, Vestbo J. Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. Respir Res. 2009 Jun 30;10:59. 26 Waschki B, Kirsten A, Holz O, Müller KC, Meyer T, Watz H, Magnussen H. Physical Activity Is the Strongest Predictor of All-Cause Mortality in Patients With COPD. A Prospective Cohort Study. Chest 2011;140:331-42.

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27 Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD Assessment Test. Eur Respir J 2009;34:648-54. 28 Rennard SI, Calverley P. Rescue! Therapy and the paradox of the Barcalounger. Eur Respir J 2003;21:916-7. 29 Garcia-Aymerich J, Serra Pons I, Mannino DM, Maas AK, Miller DP, Davis KJ. Lung function impairment, COPD hospitalisations and subsequent mortality. Thorax 2011;66:585-90. 30 Almagro P, Cabrera FJ, Diez J, Boixeda R, Ortiz B, Murio C, Soriano JB, and Working Group on COPD of the Spanish Society of Internal Medicine. Comorbidities and short-term prognosis in patients hospitalized for acute exacerbation of COPD. The ESMI study. Chest 2012 (published ahead of print April 5, 2012, doi:10.1378/chest.11-2413). 31 Mannino DM, Diaz-Guzman E. Interpreting lung function data using 80% predicted and fixed thresholds identifies patients at increased risk of mortality. Chest 2012;141:73-80. 32 López-Campos JL. Treatment strategies in chronic obstructive pulmonary disease: a proposal for standardization. Arch Bronconeumol 2010;46:617-20. 33 Nagai A. Guidelines for the diagnosis and management of chronic obstructive pulmonary disease: 3rd edition. Nihon Rinsho 2011;69:1729-34.

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Figure 1. Distribution of COCOMICS participants by old GOLD, and new GOLD, by cohort A) Old GOLD

Mild

Moderate

Severe

Very Severe

GOLD old

Bars show percents

Galdakao

Pam plona

Sevi l la

T eneri fe

Zaragoza I

Zaragoza II

Requena I

Requena II

T errassa III

T errassa I

T errassa II

Hospital

0%

25%

50%

75%

100%

Perc

en

t

B) New GOLD 2011

A

B

C

D

Gold11

Bars s how percents

Galdakao

Pam plona

Sevi l la

T eneri fe

Zaragoza I

Zaragoza II

Requena I

Requena II

T errassa III

T errassa I

T errassa II

Hospital

0%

25%

50%

75%

100%

Perc

en

t

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Figure 2. Ten-year survival (Kaplan-Meier curves) of COCOMICS participants by old GOLD and new GOLD

A) Old GOLD Cox model adjusted by cohort HR (95% CI) COPD old GOLD II 1.78 (1.29-2.46) COPD old GOLD III 2.84 (2.06-3.92) COPD old GOLD IV 4.05 (2.87-5.72)

B) New GOLD 2011 Cox model adjusted by cohort (differences between stages B and C disappears). HR (95% CI) COPD new GOLD B 1.70 (1.38-2.10) COPD new GOLD C 1.69 (1.39-2.08) COPD new GOLD D 2.79 (2.35-3.32)

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Figure 3. Impact in mortality if the entry defining criteria by GOLD 2011, is either spirometry, or exacerbations, or both

Cox model adjusted by cohort Only spirometry 1 Only exacerbations 0.98 (0.68-1.41) Both 1.56 (1.27-1.91)

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ONLINE SUPPLEMENT

Distribution and prognostic validity of the new GOLD grading

classification

Joan B. Soriano, M.D.,1 Inmaculada Alfageme, M.D.,2 Pere Almagro, M.D.,3

Ciro Casanova, M.D.,4 Cristobal Esteban, M.D.,5 Juan J. Soler-Cataluña, M.D.,6

Juan P. de Torres, M.D.,7 Pablo Martinez-Camblor, Ph.D.,8 Marc Miravitlles,

M.D.,9 Bartolome R. Celli, M.D.,10 and Jose M. Marin, M.D.11

1 Fundación Caubet-Cimera Illes Balears, Bunyola, Spain; 2 Hospital

Universitario Valme, Sevilla; 3 Internal Medicine, Hospital Universitari Mutua de

Terrassa, Universitat de Barcelona, Barcelona; 4 Hospital Nuestra Señora de la

Candelaria, Tenerife; 5 Hospital Galdakao-Usansolo, Galdakao, Bizkaia

6 Unidad de Neumología, Servicio de Medicina Interna, Hospital General de

Requena, Valencia; 7 Clınica Universidad de Navarra, Pamplona; 8 CAIBER,

Oficina de Investigación Biosanitaria de Asturias, Oviedo; 9 Institut

d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic,

Barcelona, Spain; 10 Harvard University, Brigham and Women's Hospital,

Pulmonary and Critical Care Medicine, Boston, MA, USA; 11 Hospital

Universitario Miguel Servet, Zaragoza, Spain

Author for correspondence: Dr. Joan B Soriano

Director, Program of Epidemiology & Clinical Research

CIMERA. Recinte Hospital Joan March, Carretera Soller Km 12.

07110 - Bunyola, Illes Balears; Spain

Email: [email protected]

Tel: +34 971 14 84 37 Fax: +34 971 14 84 42

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e-Table 1. Distribution of the re-classification of COPD population from the old GOLD staging to the new GOLD grading

new GOLD grading

Total A B C D

Count

old GOLD staging

Mild 225 65 2 10 302

Moderate 837 446 43 83 1409

Severe 0 0 455 656 1111

Very Severe 0 0 60 273 333

Total 1062 511 560 1022 3155

% of old GOLD staging

old GOLD staging

Mild 74.5% 21.5% .7% 3.3% 100.0%

Moderate 59.4% 31.7% 3.1% 5.9% 100.0%

Severe .0% .0% 41.0% 59.0% 100.0%

Very Severe .0% .0% 18.0% 82.0% 100.0%

Total 33.7% 16.2% 17.7% 32.4% 100.0%

% of new GOLD grading

old GOLD staging

Mild 21.2% 12.7% .4% 1.0% 9.6%

Moderate 78.8% 87.3% 7.7% 8.1% 44.7%

Severe .0% .0% 81.3% 64.2% 35.2%

Very Severe .0% .0% 10.7% 26.7% 10.6%

Total 100.0% 100.0% 100.0% 100.0% 100.0%

% of total

old GOLD staging

Mild 7.1% 2.1% .1% .3% 9.6%

Moderate 26.5% 14.1% 1.4% 2.6% 44.7%

Severe .0% .0% 14.4% 20.8% 35.2%

Very Severe .0% .0% 1.9% 8.7% 10.6%

Total 33.7% 16.2% 17.7% 32.4% 100.0%

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e-Figure 1. Ten-year survival (Kaplan-Meier curves) of COCOMICS participants by new GOLD, and old GOLD, by cohort (subfigures A to J) A) Galdakao: NOTE: It has a maximum follow-up of five years. Only one

individual in GOLD I

B) Pamplona: NOTE: Most Pamplona participants are in QBODE = 1.

C) Seville: NOTE: It has a maximum follow-up of four years. Only one individual in GOLD I.

D) Tenerife:

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E) Zaragoza I: NOTE: There are no deaths in GOLD I

F) Zaragoza II:

G) Requena II: NOTE: Time scale changed to 100 months maximum. Note also that in Requena I there were few deaths with absolute inconsistency by survival curves, so graphs are not presented in here

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H) Terrassa I:

I) Terrassa II: NOTE: It has only two patients in new GOLD B

J) Terrassa III: NOTE: Time scale changed to 100 months maximum

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Re-analysis, as per DISCUSION section:: A posteriori we re-pooled together the databases of Sevilla and Requena, the two COCOMICS cohorts that systematically collected all types of COPD exacerbations and that we considered had the greatest validity and similar definitions of ambulatory COPD exacerbations. For this re-analysis, ambulatory COPD exacerbations were defined as those COPD exacerbations that did not require a hospitalization, that is they only required an ER visit or a GP or other doctor attention. We started this re-analysis with a population of 899 individuals from Sevilla and Requena, in whom we had a minimum data set to establish their severity grading according to GOLD 2011 in 766, shown next in Table R1-1. Note that in this Table we are using the same approach as in our original analytical approach, that is COPD hospitalizations only: Table R1-1. Distribution in GOLD grades

GOLD 2011 grading with only COPD hospitalizations n Valid %

Cummulative %

A 146 19,1 19,1

B 70 9,1 28,2

C 236 30,8 59,0

D 314 41,0 100,0

Total 766 100,0

As per our original analytical approach, 28.2% of the sample were in Low Risk GOLD 2011 patient groups (19.1% in A and 9.1% in B), and therefore, they were susceptible to change upwards (A to C and B to D) if we were considering also ambulatory COPD exacerbations. In Table R1-2, we show the re-Distribution of GOLD grades if we consider those individuals with two or more COPD ambulatory exacerbations: Tabla R1-2. Re-Distribution of GOLD grades if we consider COPD ambulatory exacerbations

Number of ambulatory

exacerbations Total

0 or 1 2+

GOLD 2011 grading with only COPD hospitalizations

A 70 (47.9) 76 (52.1) 146

B 32 (45.7) 38 (54.3) 70

C 64 (27.1) 172 (72.9) 236

D 79 (25.2) 235 (74.8) 314

Total 245 (32.0) 521 (68.0) 766

As it can be seen in Table R1-2, from the 766 individuals assessed, 114 (14.9%) would actually change group, that is 76 (9.9%) from A to C, and 38 (5.0%) from B to D. Given this is a subgroup analysis and a posteriori, we are uncertain if this 14.9% change from low risk to high risk grades can be extrapolated to all eleven cohorts in COCOMICS, or other patient groups.

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Finally, the association with the outcome death is presented in Table R1-3, and in Figure R1-1. As expected, it can be seen that the association of GOLD 2011 grading with death turns out much weaker when we include COPD ambulatory exacerbations to establish the GOLD 2011 grades. It appears confirmatory that taking into account COPD exacerbations that do not require hospitalization modify the GOLD grading severity classification, in 14.9% of patients here, but they do not modify the poor survival predictability of the GOLD 2011 grading.

Table R1-3

Hazard Ratio of death with reference to GOLD 2011 grading with only COPD hospitalizations HR 95,0% CI

Lower Upper

GOLD 2011 B 1,64 ,977 2,754 GOLD 2011 C 1,643 1,094 2,467

GOLD 2011 D 2,030 1,388 2,971

Hazard Ratio of death with reference to GOLD 2011 grading with 2+ ambulatory exacerbations HR 95,0% CI

Lower Upper

GOLD 2011 B 1,699 ,876 3,295 GOLD 2011 C ,946 ,593 1,509

GOLD 2011 D 1,337 ,855 2,092

Figure R1-1. Survival (Kaplan-Meier) curves of COCOMICS participants in Sevilla and Requena by GOLD 2011 grades. A) with 2+ ambulatory exacerbations and B) with only COPD hospitalizations

A) B)

Because our conclusions are unchanged, we propose to maintain our current analytical approach, taking into account ONLY the COPD hospitalizations to determine COPD exacerbations, with all the above mentioned limitations.

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In retrospect, overall it is concluded in this re-analysis that ambulatory COPD exacerbations are truly less severe than COPD hospitalizations, likely by having a subjective component (via the patient) and/or by the system (a doctor in a universal, free-for all-system as Spain decided not to admit that patient), and therefore ambulatory COPD exacerbations predict death less well than COPD hospitalizations.

June 18, 2012

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